Ab initio Designed Antimicrobial Peptides Against Gram-Negative Bacteria

Antimicrobial peptides (AMPs) are ubiquitous amongst living organisms and are part of the innate immune system with the ability to kill pathogens directly or indirectly by modulating the immune system. AMPs have potential as a novel therapeutic against bacteria due to their quick-acting mechanism of...

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Autores principales:	Shravani S. Bobde, Fahad M. Alsaab, Guangshuan Wang, Monique L. Van Hoek
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	ab initio antimicrobial peptide design computational prediction models Gram-negative bacteria Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e41d52ebe84445eebeec83292ebc5df6
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spelling	oai:doaj.org-article:e41d52ebe84445eebeec83292ebc5df62021-11-16T07:46:12ZAb initio Designed Antimicrobial Peptides Against Gram-Negative Bacteria1664-302X10.3389/fmicb.2021.715246https://doaj.org/article/e41d52ebe84445eebeec83292ebc5df62021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fmicb.2021.715246/fullhttps://doaj.org/toc/1664-302XAntimicrobial peptides (AMPs) are ubiquitous amongst living organisms and are part of the innate immune system with the ability to kill pathogens directly or indirectly by modulating the immune system. AMPs have potential as a novel therapeutic against bacteria due to their quick-acting mechanism of action that prevents bacteria from developing resistance. Additionally, there is a dire need for therapeutics with activity specifically against Gram-negative bacterial infections that are intrinsically difficult to treat, with or without acquired drug resistance. Development of new antibiotics has slowed in recent years and novel therapeutics (like AMPs) with a focus against Gram-negative bacteria are needed. We designed eight novel AMPs, termed PHNX peptides, using ab initio computational design (database filtering technology combined with the novel positional analysis on APD3 dataset of AMPs with activity against Gram-negative bacteria) and assessed their theoretical function using published machine learning algorithms, and finally, validated their activity in our laboratory. These AMPs were tested to establish their minimum inhibitory concentration (MIC) and half-maximal effective concentration (EC50) under CLSI methodology against antibiotic resistant and antibiotic susceptible Escherichia coli and Staphylococcus aureus. Laboratory-based experimental results were compared to computationally predicted activities for each of the peptides to ascertain the accuracy of the computational tools used. PHNX-1 demonstrated antibacterial activity (under high and low-salt conditions) against antibiotic resistant and susceptible strains of Gram-positive and Gram-negative bacteria and PHNX-4 to -8 demonstrated low-salt antibacterial activity only. The AMPs were then evaluated for cytotoxicity using hemolysis against human red blood cells and demonstrated some hemolysis which needs to be further evaluated. In this study, we successfully developed a design methodology to create synthetic AMPs with a narrow spectrum of activity where the PHNX AMPs demonstrated higher antibacterial activity against Gram-negative bacteria compared to Gram-positive bacteria. Thus, these peptides present novel synthetic peptides with a potential for therapeutic use. Based on our findings, we propose upfront selection of the peptide dataset for analysis, an additional step of positional analysis to add to the ab initio database filtering technology (DFT) method, and we present laboratory data on the novel, synthetically designed AMPs to validate the results of the computational approach. We aim to conduct future in vivo studies which could establish these AMPs for clinical use.Shravani S. BobdeFahad M. AlsaabFahad M. AlsaabGuangshuan WangMonique L. Van HoekFrontiers Media S.A.articleab initioantimicrobial peptidedesigncomputational prediction modelsGram-negative bacteriaMicrobiologyQR1-502ENFrontiers in Microbiology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ab initio antimicrobial peptide design computational prediction models Gram-negative bacteria Microbiology QR1-502
spellingShingle	ab initio antimicrobial peptide design computational prediction models Gram-negative bacteria Microbiology QR1-502 Shravani S. Bobde Fahad M. Alsaab Fahad M. Alsaab Guangshuan Wang Monique L. Van Hoek Ab initio Designed Antimicrobial Peptides Against Gram-Negative Bacteria
description	Antimicrobial peptides (AMPs) are ubiquitous amongst living organisms and are part of the innate immune system with the ability to kill pathogens directly or indirectly by modulating the immune system. AMPs have potential as a novel therapeutic against bacteria due to their quick-acting mechanism of action that prevents bacteria from developing resistance. Additionally, there is a dire need for therapeutics with activity specifically against Gram-negative bacterial infections that are intrinsically difficult to treat, with or without acquired drug resistance. Development of new antibiotics has slowed in recent years and novel therapeutics (like AMPs) with a focus against Gram-negative bacteria are needed. We designed eight novel AMPs, termed PHNX peptides, using ab initio computational design (database filtering technology combined with the novel positional analysis on APD3 dataset of AMPs with activity against Gram-negative bacteria) and assessed their theoretical function using published machine learning algorithms, and finally, validated their activity in our laboratory. These AMPs were tested to establish their minimum inhibitory concentration (MIC) and half-maximal effective concentration (EC50) under CLSI methodology against antibiotic resistant and antibiotic susceptible Escherichia coli and Staphylococcus aureus. Laboratory-based experimental results were compared to computationally predicted activities for each of the peptides to ascertain the accuracy of the computational tools used. PHNX-1 demonstrated antibacterial activity (under high and low-salt conditions) against antibiotic resistant and susceptible strains of Gram-positive and Gram-negative bacteria and PHNX-4 to -8 demonstrated low-salt antibacterial activity only. The AMPs were then evaluated for cytotoxicity using hemolysis against human red blood cells and demonstrated some hemolysis which needs to be further evaluated. In this study, we successfully developed a design methodology to create synthetic AMPs with a narrow spectrum of activity where the PHNX AMPs demonstrated higher antibacterial activity against Gram-negative bacteria compared to Gram-positive bacteria. Thus, these peptides present novel synthetic peptides with a potential for therapeutic use. Based on our findings, we propose upfront selection of the peptide dataset for analysis, an additional step of positional analysis to add to the ab initio database filtering technology (DFT) method, and we present laboratory data on the novel, synthetically designed AMPs to validate the results of the computational approach. We aim to conduct future in vivo studies which could establish these AMPs for clinical use.
format	article
author	Shravani S. Bobde Fahad M. Alsaab Fahad M. Alsaab Guangshuan Wang Monique L. Van Hoek
author_facet	Shravani S. Bobde Fahad M. Alsaab Fahad M. Alsaab Guangshuan Wang Monique L. Van Hoek
author_sort	Shravani S. Bobde
title	Ab initio Designed Antimicrobial Peptides Against Gram-Negative Bacteria
title_short	Ab initio Designed Antimicrobial Peptides Against Gram-Negative Bacteria
title_full	Ab initio Designed Antimicrobial Peptides Against Gram-Negative Bacteria
title_fullStr	Ab initio Designed Antimicrobial Peptides Against Gram-Negative Bacteria
title_full_unstemmed	Ab initio Designed Antimicrobial Peptides Against Gram-Negative Bacteria
title_sort	ab initio designed antimicrobial peptides against gram-negative bacteria
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/e41d52ebe84445eebeec83292ebc5df6
work_keys_str_mv	AT shravanisbobde abinitiodesignedantimicrobialpeptidesagainstgramnegativebacteria AT fahadmalsaab abinitiodesignedantimicrobialpeptidesagainstgramnegativebacteria AT fahadmalsaab abinitiodesignedantimicrobialpeptidesagainstgramnegativebacteria AT guangshuanwang abinitiodesignedantimicrobialpeptidesagainstgramnegativebacteria AT moniquelvanhoek abinitiodesignedantimicrobialpeptidesagainstgramnegativebacteria
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Ab initio Designed Antimicrobial Peptides Against Gram-Negative Bacteria

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